Date of Award
Summer 8-12-2026
Document Type
Dissertation
Publication Status
Version of Record
Submission Date
August 2026
Department
Chemistry and Biochemistry
College Granting Degree
Charles E. Schmidt College of Science
Department Granting Degree
Chemistry and Biochemistry
Degree Name
Doctor of Philosophy (PhD)
Thesis/Dissertation Advisor [Chair]
Salvatore D. Lepore
Abstract
Five-membered cyclic ethers are prevalent in natural products, pharmaceuticals, and biologically active compounds, yet conventional syntheses often rely on scarce or toxic transition-metal catalysts and carbonyl-containing substrates. This dissertation describes a fundamentally different approach through the intramolecular addition of non-enolate carbon nucleophiles to unactivated carbon–carbon triple bonds. These transformations proceed under mild, transition-metal- and carbonyl-free conditions using inexpensive, readily available potassium tert butoxide (KOtBu), providing access to 2,5-dihydrofurans and methylideneoxolanes through authentic anionic 5-endo-dig and 5-exo-dig cyclizations.
Initial studies examined the cyclization of terminal propargyl ethers to form 2,5-dihydrofurans. Treatment with KOtBu produced cyclic ethers alongside competing 2,3-sigmatropic rearrangement products. Systematic investigation of solvent, base, temperature, reaction time, additives, and substrate structure demonstrated that the transformation occurs rapidly at room temperature and tolerates aryl, heteroaryl, and alkyl substituents. Although cyclic and rearranged products were generally formed in comparable amounts, this work established a mild cyclization of a carbonyl-free carbon nucleophile onto an unactivated alkyne, expanding the chemical space accessible beyond traditional Conia–ene and ring-closing metathesis approaches.
Mechanistic investigations using deuterium labeling, independently isolated products, and electronically varied alkyne substituents examined the origin of product selectivity. Rapid protonation of a transient vinyl anion was observed, while cyclic and allenic products did not interconvert under the reaction conditions. Changes in alkyne electronics produced little variation in product distribution. These findings are inconsistent with previously proposed stepwise mechanisms and instead support an early, likely ambimodal transition state followed by reaction-path bifurcation, directly generating cyclic and sigmatropic products along energetically competitive pathways.
Extension to homopropargyl ethers unexpectedly revealed a new anionic 5-exo-dig cyclization. These substrates efficiently underwent carbon–carbon bond formation to furnish methylideneoxolanes and 2,5-dihydrofurans, and subsequent product interconversion and derivatization demonstrated their synthetic utility.
Finally, this dissertation examines limitations in conventional alkyne cyclization nomenclature. Many transformations described as 5-endo-dig or 5-exodig involve planar enolate nucleophiles and should be distinguished based on nucleophile geometry and carbonyl placement. In contrast, the carbonyl-free reactions developed herein provide evidence for authentic 5-endo-dig and 5-exodig processes involving likely pyramidal carbanions. Collectively, this work establishes practical routes to valuable oxacycles, challenges prevailing mechanistic interpretations, and broadens understanding of carbon-nucleophile additions to unactivated alkynes.
Recommended Citation
Nugent, Kristina M., "CYCLIZATIONS OF UNACTIVATED C–C TRIPLE BONDS VIA PYRAMIDAL CARBANIONS: REDEFINING 5-EXO- AND 5-ENDO-DIG PROCESSES TOWARD CYCLIC ETHERS UNDER TRANSITION-METAL- AND CARBONYL-FREE CONDITIONS" (2026). Electronic Theses and Dissertations. 421.
https://digitalcommons.fau.edu/etd_general/421